BABE Concept 20April2007[2]

8/4/2019 BABE Concept 20April2007[2]

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Bioavailability and

Bioequivalence: General

concepts and overviewAriya Khunvichai, Ph.D.20 April 2007


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WHAT IS IT???

HOW IS IT???WHY IS IT???

REGULATION VERSUS PHARMACEUTICAL COMP.


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Facts Generic drugs are safe and effective

alternatives to brand name prescriptions

Generic drugs can help both consumers and

the government reduce the cost ofprescription drugs


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NDA vs. ANDA Review ProcessOriginal Drug

NDA Requirements

1. Chemistry

2. Manufacturing

3. Controls

4. Labeling

5. Testing

6. Animal Studies

7. Clinical Studies

(Bioavailability/Bioequivalence)

Generic Drug

ANDA Requirements

1. Chemistry

2. Manufacturing

3. Controls

4. Labeling

5. Testing

6. Bioequivalence Study (InVivo, In vitro)

Note: Generic drug applications are termed "abbreviated" because they are generallynot required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.Instead, generic applicants must scientifically demonstrate that their product is bioequivalent(i.e., performs in the same manner as the origina; drug).


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Generic Drug: Definition Same active ingredient (s)

Same route of administration

Same dosage form

Same strength

Same indications

Compares to reference listed drug (RLD)


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Bioequivalence (BE): Definitionthe absence of a significant difference in the rateand extent to which the active ingredient or activemoiety in pharmaceutical equivalents orpharmaceutical alternatives becomes available atthe site of drug action when administered at thesame molar dose under similar conditions inan appropriately designed study

.CDER U.S. Food & Drug Administration


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Bioequivalence

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Time (hours)

Concentration(ng/mL)

Test/Generic

Reference/Brand


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Goals of BEUltimate: Bioequivalence studies impact of changes tothe dosage form process after pivotal studies commenceto ensure product on the market is comparable tothat upon which the efficacy is based Establish that a new formulation has therapeutic equivalence in the rate

and extent of absorption to the reference drug product. Important for linking the commercial drug product to clinical trial

material at time of NDA Important for post-approval changes in the marketed drug formulation


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Scheme of Oral Dosage Form

Human Intestinal

Absorption (HIA)

Oral Bioavailability (%F)

1,2 Stability + Solubility3 Passive + Active Tr.

4 Pgp efflux + CYP 3A4


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Bioavailability The extent and rate at which its active moiety

is delivered from pharmaceutical form andbecomes available in the systemic circulation

(quantifies ABSORPTION = ?, Reasons for poor F)

Pharmacokineticsconc. vs time

Conc.(mg

/L)

Time (h)

0 25

0.0


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The true dose is not the drug swallowed;BUT is the drug available to exert its effect. Dissolution Absorption Survive metabolismMay have a drug with very low bioavailability Dosage form or drug may not dissolve readily Drug may not be readily pass across biological

membranes (i.e. be absorbed) Drug may be extensively metabolized during

absorption process (first-pass, gut wall, liver)Important component of overall variability Variable bioavailability may produce variable

exposure

Why do we care about BIOAVAILABILITY?


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Extent of absorption is reflected by AUC

Rate of absorption, ka, is reflected by TmaxBoth Rate and Extent of absorption affect CmaxLeads to 4 possible relative scenarios: (R) Rapid, (E) Complete Absorptionyields a short Tmax, high Cmax, high AUC (R) Rapid, (E) incomplete absorptionyields a short Tmax, low Cmax, low AUC (R) Slow, (E) complete absorptionyields a long Tmax, high Cmax, high AUC (R) Slow, (E) incomplete absorptionyields a long Tmax, low Cmax, low AUC

Rate versus Extent of Absorption


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Bioavailability IV???

Bench mark for bioequivalence

How to calculate?


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Clinical/PD Dose-Response

Bioequivalence studies assess in vivo impact of changes tothe dosage form/process after pivotal studies commence toensure product on the market is comparable to that uponwhich the efficacy is based

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Theophylline Concentration[mg/L]

F

EV1

(%

normal)

Mitenko & Ogilvie NEJM 289:600-3, 1973


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FDA Draft-Guidance for Industry (1997)Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products

New Dosage Form of a Previously Studied Drug

In some cases, modified release dosage forms may beapproved on the basis ofpharmacokinetic data linking

the new dosage form from a previously studiedimmediate-release dosage form. Because thepharmacokinetic patterns of controlled-release andimmediate release dosage forms are not identical, it is

generally important to have some understanding of therelationship of blood concentration to responsetoextrapolate to the new dosage form.


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Why do we need Bioequivalence studies? No clinical studies have been performed in

patients with the Generic Product to supportits Efficacy and Safety.

With data to support similar in vivoperformance (= Bioequivalence)Efficacy and Safety

data can be extrapolated from the InnovatorProduct to the Generic Product.


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Approaches to Determining BE (21 CFR320.24) In vivo measurement of active moiety in

biologic fluid

In vivopharmacodynamic comparison

(Topical Corticosteroid)

In vivo clinical comparison (Nasalsuspensions)

In vitro comparison(Nasal Solution, Topicalsolution, Oral solution)


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Study Design: Basic design consideration Minimize variability not attributable to

formulations

Minimize bias

To compare performance of two products!!!


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Study Designs Single-dose, two-way crossover, fasted Single-dose, two-way crossover, fed

Alternative Single-dose, parallel, fasted (Long half-life)

Single-dose, replicate design (Highly Variable

Drugs) Multiple-dose, two-way crossover, fasted

(Less Sensitive, non-linear kinetic)

Parallel or crossover?, Fasted or Fed?, Single or Multiple?, Replicate or nonreplicate?


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Duration of washout period for cross-overdesign

- should be approximately > 5 times the

plasma apparent terminal half-life

- However, should be adjusted accordingly fordrugs with complex kinetic model

Study Designs


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Sample size determination

- significant level ( = 0.05)

- 20% deviation from the reference product

- power > 80%

Sample time determination

- adequate data points around tmax

- 3 or more time of t1/2 to around AUC0-t = atleast 80% AUC0-inf

Study Designs


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Subjects? (Inclusion/exclusion criteria)

LABEL

Study Designs

(such as)Healthy subjects (male and female)18-55 years old, BMI = 18 25 kg/m2Non-smokers/without a history of alcohol or drug abuseMedical history/Clinical Lab test values must be within normal ranges

ContraindicationRefrain from the concomitants use of any medications or food interact withGI, renal, liver function from 28 days prior study Day1 through the safetyfollow up-visit.


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Study Design: Case 1Please conduct BE study of two brands of drug A in TabletInformation?

PK informationhalf-life = 10 hrsLow within subjects variability =~ 10-15%Drug mechanisms


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Statistical Analysis(Two one-sided Tests Procedure) AUC (Extent) and Cmax(Rate) Log

transformation- 90% Confidence Intervals (CI) of thedifference in Log (AUCt)Log (AUCR) must fit

between 80%-125%


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Statistical Analysis 80%-125% What does this mean?

Can there be a 46% difference?

What is a point estimate?

What is a confidence interval?


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Statistical analysis BE criteria

-Two one-sides tests procedure

Test (T) is notsignificantly less than reference

Reference (R) is not significantly less than test

Significant difference is 20% ( = 0.05 significance level)

T/R = 80/100 = 80%, or 100/80 =125%


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BE Results (90% CI)

T/R (%)80% 125%

Demonstrate BE

Fail to Demonstrate BE

Fail to Demonstrate BIE

Demonstrate BIE Demonstrate BIE


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Problems of 22 Crossover Design

Overparameterization

Carry-over effect is confounded

If carryover effect exists, the drug effectcannot be estimated correctly


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Screening ofVolunteers

ClinicalChemistry

ClinicalResearch

Implementation ofQUALITY SYSTEMS

Bioanalytical

Project

Management

Technology

Services

Pharmacokinetics& Biostatistics

Quality

Assurance

How to insured?


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In vivo BE InspectionsCovers clinical and analytical components

Study design Issues

Analytical method


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Bioanalytical Method ValidationMethod Validation should include

Accuracy

Precision

Sensitivity

Specificity

Recovery

Stability


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Accuracy

Closeness of determined valueto the true

Value

The acceptance criteria is mean value < 15%deviation from the true value.

At LOQ, 20% deviation is acceptable

Bioanalytical Method Validation


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Precision

The closeness of replicate determinations of

a sample byan assay

The acceptance criteria is < 15% CV, at

20% LOQ



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Selectivity

Ability of the method to measure only what it

is intended to measure in the presence of

other components in the sample. Blank

samples of the biological matrix should be

tested for the interfering peak.



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Recovery

The extraction efficiency of an analytical

process, reported as an percentage of the

known amount of an analyte. Recovery does

not have to be 100% but the extent of

recovery of internal standard and analyte

should be consistent.



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Stability

During, sample collection , sample storage

and sample analysis process, the stability of

drug in matrix should be conducted



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Thank you and Questions??


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Back up slides


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Statistical Method: Case 1


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Crossover Design 2x2 Crossover design A single-dose bioequivalence study is performed in

normal, healthy, adult volunteers.

18 subjects are hired (Male or Female?).

The subjects are randomly selected for each groupand the sequence of drug administration is randomlyassigned.

One-week washout periods Fasted or Fed?

Study Design: Case 1

Documents

BABE Concept 20April2007[2]